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Guilan Quan,1 Boyi Niu,1 Vikramjeet Singh,1 Yixian Zhou,1 Chuan-Yu Wu,2 Xin Pan,1 Chuanbin Wu1 1School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China; 2Department of Chemical and Process Engineering, University of Surrey, Guildford, UK Abstract: Solid self-emulsifying drug delivery system (SSEDDS), which incorporates liquid SEDDS into a solid dosage form, has been recently introduced to improve the oral bioavailability of poorly water-soluble drugs. However, supersaturated drug generated by SSEDDS is thermodynamically unstable and tends to precipitate rapidly prior to absorption, resulting in compromised bioavailability. The aim of this study was to construct a novel supersaturated SSEDDS (super-SSEDDS) by combining SSEDDS with appropriate precipitation inhibitor. Fenofibrate (FNB), a sparingly soluble drug, was selected as a model drug in this study. An optimized SSEDDS was prepared by solvent evaporation by using mesoporous silica Santa Barbara Amorphous-15 as the inert carrier. Supersaturation assay was conducted to evaluate the precipitation inhibition capacity of different polymers, and the results showed that Soluplus® could retard the FNB precipitation more effectively and sustain a higher apparent concentration for ~120 min. This effect was also clearly observed in the dissolution profiles of FNB from SSEDDS under supersaturated condition. The study of the mechanism suggested that the inhibition effect might be achieved both thermodynamically and kinetically. The area under the concentration–time curve of the super-SSEDDS was 1.4-fold greater than that of SSEDDS in the absence of Soluplus, based on an in vivo pharmacokinetic study conducted in beagle dogs. This study has demonstrated that the approach of combining SSEDDS with Soluplus as a supersaturation stabilizer constitutes a potential tool to improve the absorption of poorly water-soluble drugs. Keywords: Soluplus, supersaturation, fenofibrate, mesoporous silica, poorly water-soluble drugs

Dynamic softening behaviors of a promising biomedical Ti-13Nb-13Zr alloy under hot deformation conditions across dual phase α + β and single phase β regions were quantitatively characterized by establishing corresponding dynamic recovery (DRV) and dynamic recrystallization (DRX) kinetic models. A series of wide range hot compression tests on a Gleeble-3500 thermo-mechanical physical simulator were implemented under the strain rate range of 0.01-10 s−1 and the temperature range of 923-1173 K. The apparent differences of flow stress curves obtained in dual phase α + β and single phase β regions were analyzed in term of different dependence of flow stress to temperature and strain rate and different microstructural evolutions. Two typical softening mechanisms about DRV and DRX were identified through the variations of a series of stress-strain curves acquired from these compression tests. DRX is the dominant softening mechanism in dual phase α + β range, while DRV is the main softening mechanism in single phase β range. The DRV kinetic model for single phase β region and the DRX kinetic model for dual phase α + β region were established respectively. In addition, the microstructures of the compressed specimens were observed validating the softening mechanisms accordingly.

Linghui Dian,1,2,* Zhiwen Yang,3,* Feng Li,1 Zhouhua Wang,1 Xin Pan,1 Xinsheng Peng,2 Xintian Huang,1 Zhefei Guo,1 Guilan Quan,1 Xuan Shi,1 Bao Chen,1 Ge Li,4 Chuanbin Wu1,41School of Pharmaceutical Sciences, Sun Yat-Sen University, University Town, Guangzhou, People’s Republic of China; 2School of Pharmaceutical Sciences, Guangdong Medical College, Dongguan, People’s Republic of China; 3Department of Gastroenterology, Songjiang Branch of the Affiliated First People’s Hospital of Shanghai Jiaotong University, Shanghai, People’s Republic of China; 4Guangdong Research Center for Drug Delivery Systems, Guangzhou, People’s Republic of China*These authors contributed equally to this workAbstract: In order to improve the oral bioavailability of ibuprofen, ibuprofen-loaded cubic nanoparticles were prepared as a delivery system for aqueous formulations. The cubic inner structure was verified by cryogenic transmission electron microscopy. With an encapsulation efficiency greater than 85%, the ibuprofen-loaded cubic nanoparticles had a narrow size distribution around a mean size of 238 nm. Differential scanning calorimetry and X-ray diffraction determined that ibuprofen was in an amorphous and molecular form within the lipid matrix. The in vitro release of ibuprofen from cubic nanoparticles was greater than 80% at 24 hours, showing sustained characteristics. The pharmacokinetic study in beagle dogs showed improved absorption of ibuprofen from cubic nanoparticles compared to that of pure ibuprofen, with evidence of a longer half-life and a relative oral bioavailability of 222% (P < 0.05). The ibuprofen-loaded cubic nanoparticles provide a promising carrier candidate with an efficient drug delivery for therapeutic treatment.Keywords: ibuprofen, cubic nanoparticles, oral drug delivery, bioavailability

Zhouhua Wang,1,2 Bao Chen,1 Guilan Quan,1 Feng Li,1 Qiaoli Wu,1 Linghui Dian,1 Yixuan Dong,1 Ge Li,2 Chuanbin Wu1,21School of Pharmaceutical Sciences, 2Research and Development Center of Pharmaceutical Engineering, Sun Yat-sen University, Guangzhou, People’s Republic of ChinaBackground and methods: The aim of this study was to develop an immediate-release pellet formulation with improved drug dissolution and adsorption. Carbamazepine, a poorly water-soluble drug, was adsorbed into mesoporous silica (SBA-15-CBZ) via a wetness impregnation method and then processed by extrusion/spheronization into pellets. Physicochemical characterization of the preparation was carried out by scanning electron microscopy, transmission electron microscopy, nitrogen adsorption, small-angle and wide-angle x-ray diffraction, and differential scanning calorimetry. Flowability and wettability of the drug-loaded silica powder were evaluated by bulk and tapped density and by the angle of repose and contact angle, respectively. The drug-loaded silica powder was formulated into pellets to improve flowability.Results: With maximum drug loading in SBA-15 matrices determined to be 20% wt, in vitro release studies demonstrated that the carbamazepine dissolution rate was notably improved from both the SBA-15 powder and the corresponding pellets as compared with the bulk drug. Correspondingly, the oral bioavailability of SBA-15-CBZ pellets was increased considerably by 1.57-fold in dogs (P < 0.05) compared with fast-release commercial carbamazepine tablets.Conclusion: Immediate-release carbamazepine pellets prepared from drug-loaded silica provide a feasible approach for development of a rapidly acting oral formulation for this poorly water-soluble drug and with better absorption.Keywords: ordered mesoporous silica, poorly water-soluble drug, carbamazepine, extrusion, spheronization, pellets, bioavailability

Bao Chen1,2, Zhouhua Wang1, Guilan Quan1, Xinsheng Peng1, Xin Pan1, Rongchang Wang1, Yuehong Xu1, Ge Li2, Chuanbin Wu1,21School of Pharmaceutical Sciences, 2Research and Development Center of Pharmaceutical Engineering, Sun Yat-sen University, Guangzhou, People’s Republic of ChinaBackground: A liquisolid technique has been reported to be a new approach to improve the release of poorly water-soluble drugs for oral administration. However, an apparent limitation of this technique is the formulation of a high dose because a large amount of liquid vehicle is needed, which finally results in a low-dose liquisolid formulation. Silica as an absorbent has been used extensively in liquisolid formulations. Although nanoparticle silica can be prepared and used to improve liquid adsorption capacity, loading a high dose of drug into a liquisolid is still a challenge. With the aim of improving adsorption capacity and accordingly achieving high drug loading, ordered mesoporous silica with a high surface area and narrow pore size distribution was synthesized and used in a liquisolid formulation.Methods: Ordered mesoporous silica was synthesized and its particle size and morphology were tailored by controlling the concentration of cetyltrimethyl ammonium bromide. The ordered mesoporous silica synthesized was characterized by transmission electron microscopy, scanning electron microscopy, Fourier transform infrared spectroscopy, small-angle x-ray diffraction, wide angle x-ray diffraction, and nitrogen adsorption-desorption measurements. The liquid adsorption capacity of ordered mesoporous silica was subsequently compared with that of conventional silica materials using PEG400 as the model liquid. Carbamazepine was chosen as a model drug to prepare the liquisolid formulation, with ordered mesoporous silica as the adsorbent material. The preparation was evaluated and compared with commercially available fast-release carbamazepine tablets in vitro and in vivo.Results: Characterization of the ordered mesoporous silica synthesized in this study indicated a huge Brunauer–Emmett–Teller surface area (1030 m2/g), an ordered mesoporous structure with a pore size of 2.8 nm, and high adsorption capacity for liquid compared with conventional silica. Compared with fast-release commercial carbamazepine tablets, drug release from the liquisolid capsules was greatly improved, and the bioavailability of the liquisolid preparation was enhanced by 182.7%.Conclusion: Ordered mesoporous silica is a potentially attractive adsorbent which may lead to a new approach for development of liquisolid products.Keywords: ordered mesoporous silica, poorly water-soluble drug, carbamazepine, liquisolid, bioavailability

Increasing the oral bioavailability of poorly water-soluble carbamazepine using immediate-release pellets supported on SBA-15 mesoporous silica Wang Z, Chen B, Quan G, et al. International Journal of Nanomedicine. 2012;7:5807–5818.This paper was published without the Supplementary materials.Read the original article

We assessed Ki-ras mutations by single-strand conformation polymorphism followed by DNA sequencing, p53 expression by immunohistochemistry, ploidy status, and S-phase fraction in 66 stage II and 163 stage III colon cancer patients enrolled on a randomized trial of surgery followed by observation or adjuvant levamisole or 5-fluorouracil (5FU) plus levamisole (Intergroup Trial 0035) to see whether these factors were independently associated with survival or with differential effects of adjuvant therapy. A Cox proportional hazards survival model was used to describe marker effects and therapy by marker interactions, with adjustment for the clinical covariates affecting survival. A Bonferroni adjustment was used to account for multiple testing. Mutation of the Ki-ras gene was found in 41% of the cancers and was associated with a poor prognosis in stage II but not stage III. In stage II, 7-year survival was 86% versus 58% in those with wild type versus Ki-ras mutations. After adjustment for treatment and clinical variables, the hazard ratio (HR) for death was 4.5; 95% confidence interval (CI), 1.7-12.1 (P = 0.012). p53 overexpression was found in 63% of cancers and was associated with a favorable survival in stage III but not stage II. Seven-year survival in stage III was 56% with p53 overexpression versus 43% with no p53 expression (HR, 2.2; 95% CI, 1.3-3.6; P = 0.012). Aneuploidy was more common in stage III than in stage II (66 versus 47%; P = 0.009) but was not independently related to survival in either group. The proliferative rate was greater in aneuploid than in diploid cancers but was not related to survival. There was no benefit of adjuvant therapy in stage II nor in any of the stage II subgroups defined by mutational status. In stage III, adjuvant therapy with 5FU plus levamisole improved 7-year survival in patients with wild-type Ki-ras (76 versus 44%; HR, 0.4; 95% CI, 0.2-0.8) and in those without p53 overexpression (64 versus 26%; HR, 0.3; 95% CI, 0.1-0.7). Adjuvant therapy did not benefit those with Ki-ras mutations or p53 overexpression. The effects of adjuvant therapy did not differ according to ploidy status or proliferative rate. Ki-ras mutation is a significant risk factor for death in stage II, and the absence of p53 expression is a significant risk factor for death in stage III colon cancer after adjustment for treatment and clinical covariates. Exploratory analyses suggest that patients with stage III colon cancer with wild-type Ki-ras or no p53 expression benefit from adjuvant 5FU plus levamisole, whereas those with Ki-ras mutations or p53 overexpression do not. An independent study will be required to determine whether response to adjuvant therapy in colon cancer depends on mutational status.

Abstract The present study aims to explore the influence of field cognitive style on the false memory of Chinese characters. Based on the related literature, this paper used Cognitive Style Figure Test (CSFT) to investigate the field cognitive style of college student and test the differences of field cognitive style in demographic variables. Using the DRM paradigm, with Chinese characters lists as experimental material. This study was to inspect whether Chinese semantic/tonetic association has any effect on false memory, and whether there is any interaction between field cognitive style and Chinese character component on it. The results showed that: (a) there were significant differences between male and female in the recognition rate of symbol types, with the recognition rate of tonetic symbol type characters being generally higher than that of semantic symbol type; (b) Chinese semantic/tonetic associations had an effect on false memory and gender has a significant difference in the recognition of critical-lures; (c) field cognitive style had no statistically significant difference in recognition rate on character component type and characters type (old characters, filler characters, and critical-lures); (d) individuals with different field cognitive styles differed significantly in the rate of misrecognition of critical-lures for semantic symbols.

Objectives Cervical alignment and range of motion (ROM) changes after cervical spine surgery are related to cervical biomechanical and functions. Few studies compared these parameters between posterior laminoplasty and anterior 3‐level hybrid surgery incorporating anterior cervical discectomy and fusion (ACDF) with cervical disc replacement (CDR). This study is aimed to detect the differences of cervical alignment and ROM changes of the two surgeries in a matched‐cohort study. Methods From January 2018 and May 2020, 51 patients who underwent 3‐level hybrid surgery incorporating ACDF with ACDR were included. A 1:1 match of the patients who underwent cervical laminoplasty based on age, gender, duration of symptoms, body mass index, and cervical alignment type was utilized as control group. General data (operative time, blood loss, etc.), Japanese Orthopaedic Association (JOA) score, VAS (Visual Analog Score), NDI (The Neck Disability Index), cervical sagittal alignment, and cervical range of motion (ROM) were recorded and compared. Results Both groups gained significant improvement in JOA, VAS, NDI scores postoperatively (p

Objective(s): To investigate whether 3-methyladenine (3-MA) can protect the kidney of streptozotocin (STZ) - induced diabetes mice, and explore its possible mechanism. Materials and Methods: STZ was used to induce diabetes in C57BL/6J mice. The mice were divided into normal control group (NC), diabetes group (DM), and diabetes+3-MA intervention group (DM+3-MA). Blood glucose, water consumption, and body weight were recorded weekly. At the end of the 6th week of drug treatment, 24-hour urine was collected. Blood and kidneys were collected for PAS staining to evaluate the degree of renal injury. Sirius red staining was used to assess collagen deposition. Blood urea nitrogen (BUN), serum creatinine, and 24-hour urine albumin were used to evaluate renal function. Western blot was used to detect fibrosis-related protein, inflammatory mediators, high mobility group box 1 (HMGB1)/NF-κB signal pathway molecule, vascular endothelial growth factor (VEGF), and podocin, and immunohistochemistry (IHC) was used to detect the expression and localization of autophagy-related protein and fibronectin.Results: Compared with the kidney of normal control mice, the kidney of diabetes control mice was more pale and hypertrophic. Hyperglycemia induces renal autophagy and activates the HMGB1/NF-κB signal pathway, leading to the increase of inflammatory mediators, extracellular matrix (ECM) deposition, and proteinuria in the kidney. In diabetic mice treated with 3-MA, blood glucose decreased, autophagy and HMGB1/NF-κB signaling pathways in the kidneys were inhibited, and proteinuria, renal hypertrophy, inflammation, and fibrosis were improved. Conclusion: 3-MA can attenuate renal injury in STZ-induced diabetic mice through inhibition of autophagy and HMGB1/NF-κB signaling pathway.

Abstract Background The relationship between lifestyle and migraine is complex, as it remains uncertain which specific lifestyle factors play the most prominent role in the development of migraine, or which modifiable metabolic traits serve as mediators in establishing causality. Methods Independent genetic variants strongly associated with 20 lifestyle factors were selected as instrumental variables from corresponding genome-wide association studies (GWASs). Summary-level data for migraine were obtained from the FinnGen consortium (18,477 cases and 287,837 controls) as a discovery set and the GWAS meta-analysis data (26,052 cases and 487,214 controls) as a replication set. Estimates derived from the two datasets were combined using fixed-effects meta-analysis. Two-step univariable MR (UVMR) and multivariable Mendelian randomization (MVMR) analyses were conducted to evaluate 19 potential mediators of association and determine the proportions of these mediators. Results The combined effect of inverse variance weighted revealed that a one standard deviation (SD) increase in genetically predicted Leisure screen time (LST) was associated with a 27.7% increase (95% CI: 1.14–1.44) in migraine risk, while Moderate or/and vigorous physical activity (MVPA) was associated with a 26.9% decrease (95% CI: 0.61–0.87) in migraine risk. The results of the mediation analysis indicated that out of the 19 modifiable metabolic risk factors examined, hypertension explains 24.81% of the relationship between LST and the risk of experiencing migraine. Furthermore, hypertension and diastolic blood pressure (DBP) partially weaken the association between MVPA and migraines, mediating 4.86% and 4.66% respectively. Conclusion Our research findings indicated that both LST and MVPA in lifestyle have independent causal effects on migraine. Additionally, we have identified that hypertension and DBP play a mediating role in the causal pathway between these two factors and migraine.

Abstract Rapid urbanization has resulted in the substantial population growth in metropolitan areas. However, existing research on population change of the cities predominantly draws on grid statistical data at the administrative level, overlooking the intra-urban variegation of population change. Particularly, there is a lack of attention given to the spatio-temporal change of population across different urban forms and functions. This paper therefore fills in the lacuna by clarifying the spatio-temporal characteristics of population growth in the Guangdong-Hong Kong-Macao Greater Bay Area (GBA) from 2000 to 2020 through the methods of local climate zone (LCZ) scheme and urban–rural gradients. The results showed that: (1) High population density was observed in the compact high-rise (LCZ 1) areas, with a noticeable decline along urban–rural gradients. (2) The city centers of GBA experienced the most significant population growth, while certain urban fringes and rural areas witnessed significant population shrinkage. (3) The rate of growth tended to slow down after 2010, but the uneven development of population-based urbanization was also noticeable, as urbanization and industrialization varied across different LCZ types and cities in GBA. This paper therefore contributes to a deeper understanding of population change and urbanization by clarifying their spatio-temporal contingences at landscape level.

Abstract Background Environmental temperature is critical in regulating biological functions in fish. S. prenanti is a kind of cold-water fish, but of which we have little knowledge about the metabolic adaptation and physiological responses to long-term cold acclimation. Results In this study, we determined the physiological responses of S. prenanti serum after 30 days of exposure to 6℃. Compared with the control group, the levels of TC, TG, and LDL-C in the serum were significantly (P

Milk was a source of important nutrients for humans and was especially important for children and adolescents. The modern dairy animal production pattern had contributed to residual sex steroid hormones in milk. When this milk was consumed by humans, these hormones entered the body leading to hormonal disruptions and potentially increasing the risk of various types of cancers. This article reviewed the presence of residual sex steroid hormones in milk, their potential risks on human health, and their possible association with the incidence of breast and prostate cancer. The potential linkage between dairy consumption and these cancers were described in detail. The hormones present in dairy products could affect the development and progression of these types of cancer. Sex steroid hormones could interact with different signaling pathways, influencing carcinogenic cascades that could eventually lead to tumorigenesis. Given these potential health risks, the article suggested appropriate consumption of dairy products. This included being mindful not just of the amount of dairy consumed, but also the types of dairy products selected. More scientific exploration was needed, but this review provided valuable insights for health-conscious consumers and contributed to the ongoing discussion on dietary guidelines and human health.

Abstract Background Lifestyle are closely related to migraine. However, there is a lack of studies investigating the association between Healthy lifestyle or Life’s Essential 8 (LE8) and the risk of migraine. The objective of this research was to investigate the relationship between Healthy lifestyle scores and Life’s essential 8 scores, and migraine. Methods 332,895 UK Biobank participants without migraine were included. Healthy lifestyle were assessed using seven lifestyle factors, and categorized as poor, intermediate, or ideal. LE8, based on the American Heart Association (AHA) Guidelines for Cardiovascular Health (CVH), consist of eight indicators classified as low, moderate, or high CVH. The Cox proportional hazard model was employed to examine the association between Healthy lifestyle scores, LE8 scores, and migraine, with calculations for population-attributable fraction (PAF) and cumulative incidence. Results During a median follow-up of 13.58 years, participants in intermediate (HR: 0.91; 95% CI: 0.85, 0.99) or ideal category of Healthy lifestyle (HR: 0.81; 95% CI: 0.73, 0.91) significantly reduced migraine risk compared to the poor category. Similarly, high CVH (HR: 0.73; 95% CI: 0.58, 0.92) also lowered migraine risk, while moderate CVH (HR: 0.93; 95% CI: 0.85, 1.02) did not show a difference compared to low CVH. If all individuals adhered to higher categories of Healthy lifestyle and LE8, approximately 11.38% and 22.05% of migraine cases could be prevented. Among individual lifestyle factors, maintaining an ideal body mass index (BMI), physical activity, sleep duration, sleep pattern, and sedentary time were associated with substantial reductions in migraine risk, by 5.65%, 0.81%, 10.16%, 16.39%, and 6.57%, respectively. Conclusion Our study provides evidence that poor Healthy lifestyle and Life’s Essential 8 are associated with higher risk of new-onset migraine.

Abstract Body shape phenotypes combining multiple anthropometric traits have been linked to postmenopausal breast cancer (BC). However, underlying biological pathways remain poorly understood. This study investigated to what extent the associations of body shapes with postmenopausal BC risk is mediated by biochemical markers. The study included 176,686 postmenopausal women from UK Biobank. Four body shape phenotypes were derived from principal component (PC) analysis of height, weight, body mass index, waist and hip circumferences, and waist-to-hip ratio (WHR). The four-way decomposition of the total effect was used to estimate mediation and interaction effects simultaneously as well as the mediated proportions. After 10.9 years median follow-up, 6,396 incident postmenopausal BC were diagnosed. There was strong evidence of positive associations between PC1 (general obesity) and PC2 (tall, low WHR), and BC risk. The association of PC1 with BC risk was positively mediated by testosterone and negatively by insulin-like growth factor-1 (IGF-1), with the overall proportion mediated (sum of the mediated interaction and pure indirect effect (PIE)) accounting for 11.4% (95% confidence intervals: 5.1 to 17.8%) and -12.2% (-20.5% to -4.0%) of the total effect, respectively. Small proportions of the association between PC2 and BC were mediated by IGF-1 (PIE: 2.8% (0.6 to 4.9%)), and sex hormone-binding globulin (SHBG) (PIE: -6.1% (-10.9% to -1.3%)). Our findings are consistent with differential pathways linking different body shapes with BC risk, with a suggestive mediation through testosterone and IGF-1 in the relationship of a generally obese body shape and BC risk, while IGF-1 and SHBG may mediate a tall/lean body shape-BC risk association.

Abstract We explore the controls of stress magnitude and orientation relative to bedding on the resulting morphology/topology of hydraulic fractures using a combined finite-discrete element method (FDEM). Behavior is shown conditioned by the ratio of principal stresses $$\lambda ={\sigma }_{3}/{\sigma }_{1}$$ λ = σ 3 / σ 1 and relative inclination of the bedding. When the lateral pressure coefficient ( $$\lambda$$ λ ) is less than 0.67, hydraulic fractures predominantly initiate as tensile fractures along the wellbore, aligning with the maximum principal stress direction. Conversely, for $$\lambda \ge 0.67$$ λ ≥ 0.67 , shear cracks are favored to initiate for the minor stress difference, leading to a less predictable initiation and extension direction. Simultaneously, diminished stress differences correspond to elevated reservoir breakdown pressures, displaying a linear correlation with lateral pressure coefficients and little influenced by equivalent bedding orientation. Bedding plane orientation significantly impacts the mode and morphology of hydraulic fracture propagation. Bedding parallel to the direction of the minimum principal stress ( $${\sigma }_{3}$$ σ 3 ) favors layer-penetrating and bifurcated fractures, whereas inclined bedding facilitates the emergence of numerous steering-type and capture-type fractures. Especially at steeper inclinations ( $$\beta =60^\circ$$ β = 60 ∘ ), hydraulic fractures readily extend along the bedding surface, inducing macroscopic shear slip failure. Under high-stress disparities, the breakdown pressure exhibits greater sensitivity to bedding inclination, and its influence pattern aligns with the variations in tensile strength, typically reaching maximum and minimum values at bedding inclination angles of 0° and 60°, respectively.

Abstract Background Lung cancer is cancer with the highest morbidity and mortality in the world and poses a serious threat to human health. Therefore, discovering new treatments is urgently needed to improve lung cancer prognosis. Small molecule inhibitors targeting the ubiquitin-proteasome system have achieved great success, in which deubiquitinase inhibitors have broad clinical applications. The deubiquitylase OTUD3 was reported to promote lung tumorigenesis by stabilizing oncoprotein GRP78, implying that inhibition of OTUD3 may be a therapeutic strategy for lung cancer. Results In this study, we identified a small molecule inhibitor of OTUD3, Rolapitant, by computer-aided virtual screening and biological experimental verification from FDA-approved drugs library. Rolapitant inhibited the proliferation of lung cancer cells by inhibiting deubiquitinating activity of OTUD3. Quantitative proteomic profiling indicated that Rolapitant significantly upregulated the expression of death receptor 5 (DR5). Rolapitant also promoted lung cancer cell apoptosis through upregulating cell surface expression of DR5 and enhanced TRAIL-induced apoptosis. Mechanistically, Rolapitant directly targeted the OTUD3-GRP78 axis to trigger endoplasmic reticulum (ER) stress-C/EBP homologous protein (CHOP)-DR5 signaling, sensitizing lung cancer cells to TRAIL-induced apoptosis. In the vivo assays, Rolapitant suppressed the growth of lung cancer xenografts in immunocompromised mice at suitable dosages without apparent toxicity. Conclusion In summary, the present study identifies Rolapitant as a novel inhibitor of deubiquitinase OTUD3 and establishes that the OTUD3-GRP78 axis is a potential therapeutic target for lung cancer.

High-energy gamma rays produced in inertial confinement fusion (ICF) experiments are crucial for studying implosion dynamics. These gamma rays, characterized by their extremely short durations, represent the least disturbed products of fusion, preserving vital birth information. To detect such γ-rays, ultrafast radiation detectors with high time resolution are necessary. This study introduces a newly developed Cherenkov optical image screen designed for ultra-fast gamma-ray imaging. Composed of pure quartz fiber material, the imaging screen features a single fiber pixel size of 0.6 mm and a thickness of 3 cm. Theoretical investigations explore the luminous time response and efficiency of the Cherenkov optical imaging screen under gamma-ray irradiation. Experimental validation was conducted using a steady-state gamma-ray source with an average energy of 1.25 MeV. Results demonstrate that the image screen achieves a spatial resolution limit of 0.75 mm. The temporal response exhibits a full width at half maximum of less than 0.4 ns when excited by a high-energy electron beam with a single pulse duration of several picoseconds.

Rice is the leading global staple crop. Low temperatures pose negative impacts on rice’s optimal growth and development. Rice cultivars acclimating to low temperatures exhibited improved seedling emergence under direct-seeded sowing conditions, yet little is known about the genes that regulate germination at low temperatures (LTG). In this research investigation, we’ve performed whole genome sequencing for the 273 rice plant materials. Using the best linear unbiased prediction (BLUP) values for each rice material, we identified 7 LTG-related traits and performed the efficient genetic analysis and genome-wide association study (GWAS). As a result of this, 95 quantitative trait loci (QTLs) and 1001 candidate genes associated with LTG in rice were identified. Haplotype analysis and functional annotation of the candidate genes resulted in the identification of three promising candidate genes (LOC_Os08g30520 for regulating LTG4 and LTG5, LOC_Os10g02625 for regulating LTG6, LTg7 and LTG8, and LOC_Os12g31460 for regulating LTG7, LTg8 and LTG9) involving in the regulation of LTG in rice. This research provides a solid foundation for addressing the LTG issue in rice and will be valuable in future direct-seeded rice breeding programs.

Abstract As a particularly common mineral in granites, the presence of feldspar and feldspar‐chlorite gouges at hydrothermal conditions has important implications in fault strength and reactivation. We present laboratory observations of frictional strength and stability of feldspar (K‐feldspar and albite) and feldspar‐chlorite gouges under conditions representative of deep geothermal reservoirs to evaluate the impact on fault stability. Velocity‐stepping experiments are performed at a confining stress of 95 MPa, pore pressures of 35–90 MPa, and temperatures of 120–400°C representative of in situ conditions for such reservoirs. Our experiment results indicate that the feldspar gouge exhibits strong friction (μ ∼ 0.71) at all experimental temperatures (∼120–400°C) but when T > 120°C, the frictional response transitions from velocity‐strengthening to slightly velocity‐weakening. At constant confining pressure and temperature, increasing the pore pressure increases the friction coefficient (∼0.70–0.85) and the gouge remains slightly velocity weakening. The presence of alteration‐sourced chlorite leads to a transition from velocity weakening to velocity strengthening in the mixed gouge at experimental temperatures and pore pressures. As a ubiquitous mineral in reservoir rocks, feldspar is shown to potentially contribute to unstable sliding over ranges in temperature and pressure typical in deep hydrothermal reservoirs. These findings emphasize that feldspar minerals may increase the potential for injection‐induced seismicity on pre‐existing faults if devoid of chloritization.

Deep learning has revolutionized numerous fields, notably image classification. However, conventional methods in agricultural pest recognition struggle with the long-tail distribution of pest image data, characterized by limited samples in rare pest categories, thereby impeding overall model performance. This study proposes two state-of-the-art techniques: Instance-based Data Augmentation (IDA) and Constraint-based Feature Tuning (CFT). IDA collaboratively applies resampling and mixup methods to notably enhance feature extraction for rare class images. This approach addresses the long-tail distribution challenge through resampling, ensuring adequate representation for scarce categories. Additionally, by introducing data augmentation, we further refined the recognition of tail-end categories without compromising performance on common samples. CFT, a refinement built upon pre-trained models using IDA, facilitated the precise classification of image features through fine-tuning. Our experimental findings validate that our proposed method outperformed previous approaches on the CIFAR-10-LT, CIFAR-100-LT, and IP102 datasets, demonstrating its effectiveness. Using IDA and CFT to optimize the ViT model, we observed significant improvements over the baseline, with accuracy rates reaching 98.21%, 88.62%, and 64.26%, representing increases of 0.74%, 3.55%, and 5.73% respectively. Our evaluation of the CIFAR-10-LT and CIFAR-100-LT datasets also demonstrated state-of-the-art performance.

Introduction: Current anti-rheumatic drugs are primarily modulating immune cell activation, yet their effectiveness remained suboptimal. Therefore, novel therapeutics targeting alternative mechanisms, such as synovial activation, is urgently needed. Objectives: To explore the role of Midline-1 (Mid1) in synovial activation. Methods: NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice were used to establish a subcutaneous xenograft model. Wild-type C57BL/6, Mid1-/-, Dpp4-/-, and Mid1-/- Dpp4-/- mice were used to establish a collagen-induced arthritis model. Cell viability, cell cycle, qPCR and western blotting analysis were used to detect MH7A proliferation, dipeptidyl peptidase-4 (DPP4) and Mid1 levels. Co-immunoprecipitation and proteomic analysis identified the candidate protein of Mid1 substrates. Ubiquitination assays were used to determine DPP4 ubiquitination status. Results: An increase in Mid1, an E3 ubiquitin ligase, was observed in human RA synovial tissue by GEO dataset analysis, and this elevation was confirmed in a collagen-induced mouse arthritis model. Notably, deletion of Mid1 in a collagen-induced arthritis model completely protected mice from developing arthritis. Subsequent overexpression and knockdown experiments on MH7A, a human synoviocyte cell line, unveiled a previously unrecognized role of Mid1 in synoviocyte proliferation and migration, the key aspects of synovial activation. Co-immunoprecipitation and proteomic analysis identified DPP4 as the most significant candidate of Mid1 substrates. Mechanistically, Mid1 promoted synoviocyte proliferation and migration by inducing ubiquitin-mediated proteasomal degradation of DPP4. DPP4 deficiency led to increased proliferation, migration, and inflammatory cytokine production in MH7A, while reconstitution of DPP4 significantly abolished Mid1-induced augmentation of cell proliferation and activation. Additionally, double knockout model showed that DPP4 deficiency abolished the protective effect of Mid1 defect on arthritis. Conclusion: Overall, our findings suggest that the ubiquitination of DPP4 by Mid1 promotes synovial cell proliferation and invasion, exacerbating synovitis in RA. These results reveal a novel mechanism that controls synovial activation, positioning Mid1 as a promising target for therapeutic intervention in RA.

Cadmium (Cd), a toxic element, often makes a serious threat to plant growth and development. Previous studies found that melatonin (Mel) reduced Cd accumulation and reestablished the redox balance to alleviate Cd stress in Medicago sativa L., however, the complex molecular mechanisms are still elusive. Here, comparative transcriptome analysis and biochemical experiments were conducted to explore the molecular mechanisms of Mel in enhancing Cd tolerance. Results showed that 7237 differentially expressed genes (DEGs) were regulated by Mel pretreatment to Cd stress compared to the control condition in roots of Medicago sativa L. Besides, in comparison with Cd stress alone, Mel upregulated 1081 DEGs, and downregulated 1085 DEGs. These DEGs were mainly involved in the transcription and translation of genes and folding, sorting and degradation of proteins, carbohydrate metabolism, and hormone signal network. Application of Mel regulated the expression of several genes encoding ribosomal protein and E3 ubiquitin-protein ligase involved in folding, sorting and degradation of proteins. Moreover, transcriptomic analyse suggested that Mel might regulate the expression of genes encoding pectin lyase, UDP-glucose dehydrogenase, sucrose-phosphate synthase, hexokinase-1, and protein phosphorylation in the sugar metabolism. Therefore, these could promote sucrose accumulation and subsequently alleviate the Cd damage. In conclusion, above findings provided the mining of important genes and molecular basis of Mel in mitigating Cd tolerance and genetic cultivation of Medicago sativa L.

Summary: Due to the higher and more rapid consumption of carbohydrates by cancer cells compared to normal cells, carbohydrates can be effectively employed as a targeted therapeutic strategy for tumor treatment. Here, we present a protocol for synthesizing sequence-controlled glycooligomers using both solution-phase and solid-phase systems. We outline detailed procedures for evaluating the safety and tumor-targeting properties of the sequence-controlled glycooligomers in vivo.For complete details on the use and execution of this protocol, please refer to Chen et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract The principal aim of this investigation is to identify pivotal biomarkers linked to the prognosis of osteosarcoma (OS) through the application of artificial intelligence (AI), with an ultimate goal to enhance prognostic prediction. Expression profiles from 88 OS cases and 396 normal samples were procured from accessible public databases. Prognostic models were established using univariate COX regression analysis and an array of AI methodologies including the XGB method, RF method, GLM method, SVM method, and LASSO regression analysis. Multivariate COX regression analysis was also employed. Immune cell variations in OS were examined using the CIBERSORT software, and a differential analysis was conducted. Routine blood data from 20,679 normal samples and 437 OS cases were analyzed to validate lymphocyte disparity. Histological assessments of the study's postulates were performed through immunohistochemistry and hematoxylin and eosin (HE) staining. AI facilitated the identification of differentially expressed genes, which were utilized to construct a prognostic model. This model discerned that the survival rate in the high-risk category was significantly inferior compared to the low-risk cohort (p

Abstract Gastric cancer (GC), known for its high incidence and poor prognosis, urgently necessitates the identification of reliable prognostic biomarkers to enhance patient outcomes. We scrutinized data from 375 GC patients alongside 32 non-cancer controls, sourced from the TCGA database. A univariate Cox Proportional Hazards Model (COX) regression was employed to evaluate expressions of ferroptosis-related genes. This was followed by the application of Least Absolute Shrinkage and Selection Operator (LASSO) and multivariate COX regression for the development of prognostic models. The composition of immune cell subtypes was quantified utilizing CIBERSORT, with their distribution in GC versus control samples being comparatively analyzed. Furthermore, the correlation between the expressions of Cystathionine Gamma-Lyase (CTH) and Microtubule Associated Protein 1 Light Chain 3 Beta (MAP1LC3B) and the abundance of immune cell subtypes was explored. Our bioinformatics findings underwent validation through immunohistochemical analysis. Our prognostic models integrated CTH and MAP1LC3B. Survival analysis indicated that patients categorized as high-risk, as defined by the model, exhibited significantly lower survival rates compared to their low-risk counterparts. Notably, CTH expression inversely correlated with monocyte levels, while MAP1LC3B expression showed an inverse relationship with the abundance of M2 macrophages. Immunohistochemical validation corroborated lower expressions of CTH and MAP1LC3B in GC tissues relative to control samples, in concordance with our bioinformatics predictions. Our study suggests that the dysregulation of CTH, MAP1LC3B, and the accompanying monocyte-macrophage dynamics could be pivotal in the prognosis of GC. These elements present potential targets for prognostic assessment and therapeutic intervention.

Abstract Background Endothelial-to-Mesenchymal Transformation (EndMT) plays key roles in endothelial dysfunction during the pathological progression of atherosclerosis; however, its detailed mechanism remains unclear. Herein, we explored the biological function and mechanisms of upstream stimulating factor 1 (USF1) in EndMT during atherosclerosis. Methods The in vivo and in vitro atherosclerotic models were established in high fat diet-fed ApoE−/− mice and ox-LDL-exposed human umbilical vein endothelial cells (HUVECs). The plaque formation, collagen and lipid deposition, and morphological changes in the aortic tissues were evaluated by hematoxylin and eosin (HE), Masson, Oil red O and Verhoeff-Van Gieson (EVG) staining, respectively. EndMT was determined by expression levels of EndMT-related proteins. Target molecule expression was detected by RT-qPCR and Western blotting. The release of pro-inflammatory cytokines was measured by ELISA. Migration of HUVECs was detected by transwell and scratch assays. Molecular mechanism was investigated by dual-luciferase reporter assay, ChIP, and Co-IP assays. Results USF1 was up-regulated in atherosclerosis patients. USF1 knockdown inhibited EndMT by up-regulating CD31 and VE-Cadherin, while down-regulating α-SMA and vimentin, thereby repressing inflammation, and migration in ox-LDL-exposed HUVECs. In addition, USF1 transcriptionally activated ubiquitin-specific protease 14 (USP14), which promoted de-ubiquitination and up-regulation of NLR Family CARD Domain Containing 5 (NLRC5) and subsequent Smad2/3 pathway activation. The inhibitory effect of sh-USF1 or sh-USP14 on EndMT was partly reversed by USP14 or NLRC5 overexpression. Finally, USF1 knockdown delayed atherosclerosis progression via inhibiting EndMT in mice. Conclusion Our findings indicate the contribution of the USF1/USP14/NLRC5 axis to atherosclerosis development via promoting EndMT, which provide effective therapeutic targets.

Abstract Chiral sensing of single molecules is vital for the understanding of chirality and their applications in biomedicine. However, current technologies face severe limitations in achieving single-molecule sensitivity. Here we overcome these limitations by designing a tunable chiral supramolecular plasmonic system made of helical oligoamide sequences (OS) and nanoparticle-on-mirror (NPoM) resonator, which works across the classical and quantum regimes. Our design enhances the chiral sensitivity in the quantum tunnelling regime despite of the reduced local E-field, which is due to the strong Coulomb interactions between the chiral OSs and the achiral NPoMs and the additional enhancement from tunnelling electrons. A minimum of four molecules per single-Au particle can be detected, which allows for the detection of an enantiomeric excess within a monolayer, manifesting great potential for the chiral sensing of single molecules.

While many studies have compared global precipitation datasets at national, continental, and global scales, few have evaluated these data at river basin scales. This study explored differences in precipitation estimates and trends of 12 widely applied precipitation datasets, including gauge-, satellite-, and reanalysis-based products, for the world's 6,292 river basins. Results showed that disparities between 12 precipitation datasets were considerable. A total of 3,125 river basins, with a land area of 5,989.1×104 km2, had differences in estimated annual average precipitation exceeding 500 mm yr−1, and these basins were mainly distributed in Greenland, Africa, Oceania, and West Asia. Disparities between the precipitation datasets were particularly large during the dry season when the percentage difference between the highest and lowest precipitation estimates exceeded 500% in 1,390 river basins (4,839.7×104 km2) expected due to numerical reasons. Differences in rainfall trends also varied markedly between data sources. The data products do not agree on precipitation trends for all river basins. These findings illustrate the importance of accurate precipitation data to ensure effective policy and planning in term of hydropower generation, domestic water supply, flood protection, and drought relief at river basin scales and highlight the uncertainty that exists in current global precipitation data. HIGHLIGHTS A comprehensive evaluation of global precipitation datasets was compared at the river basin scale.; Seasonal and annual differences in these precipitation datasets were compared.; Gives a sufficient explanation of which product is suitable for which river basin.;

OBJECTIVE: The aim of this study is to find an accurate and fast method to diagnose the pathogen of bronchiectasis PATIENTS AND METHODS: Ten bronchiectasic patients diagnosed with Mucoid Pseudomonas Aeruginosa (MPA) in the past two years were analyzed. Accuracy and time were compared between microbiology rapid on-site evaluation (M-ROSE) and sputum bacterial culture. RESULTS: The accuracy rate of M-ROSE in the patients is 100% consistent with bacterial culture results. The average time of M-ROSE is about 4.3 min, which is over 1000 times shorter than that of sputum bacterial culture. CONCLUSIONS: M-ROSE may be a better method for etiological diagnosis of MPA. [ABSTRACT FROM AUTHOR]

Abstract Searching for multiferroic materials with ferromagnetic (FM) and ferroelectric (FE) properties holds promise for ultra‐high‐density and low‐energy‐consumption memory device applications, but 2D materials with both properties are rare. Herein, a general strategy to achieve nonvolatile electric field control of magnetism in the bilayer (BL) α‐In2Se3 by hole doping is proposed. By first‐principles calculations, it is demonstrated that hole doping can induce robust ferromagnetism in the bilayer α‐In2Se3 due to its unique flat Mexican‐hat‐shape valence band structure. Such band edges cause van Hove singularities (VHS), and proper hole doping can lead to time‐reversal symmetry breaking. The bilayer α‐In2Se3 exhibits ferromagnetism and ferroelectricity within a wide range of doping concentrations, resulting in an unexpected multiferroic phase. Furthermore, when the electrical polarization of α‐In2Se3 flips from downward to upward, it becomes non‐magnetic (NM) from ferromagnetic states in the As‐substituted bilayer α‐In2Se3, which can work as a nonvolatile magnetic storage unit. Remarkably, the As‐substituted bilayer α‐In2Se3 exhibits an enhanced magnetic moment of 1.2 μB per AsSe due to substantial charge transfer across the interface. Notably, the mechanism of electrically controlled magnetism is elucidated as the coupling among the Mexican‐hat‐like dispersion, ferromagnetism, and ferroelectricity. The findings offer a promising strategy for electrical writing and the magnetic reading memory device.

Traditional Chinese medicine (TCM) formulae have been studied extensively in various human diseases and have proven to be effective due to their multi-component, multi-target advantage. However, its active metabolites are not clear and the specific mechanisms are not well established, which limits its scientific application. Recently, combination therapies are attracting increasing attention from the scientific community in the past few years and are considered as the next paradigm in drug discovery. Here, we tried to define a new concept of “active metabolites combination therapies (AMCT)” rules to elucidate how the bioactive metabolites from TCMs to produce their synergistic effects in this review. The AMCT rules integrate multidisciplinary technologies like molecular biology, biochemistry, pharmacology, analytical chemistry and pharmacodynamics, etc. Meanwhile, emerging technologies such as multi-omics combined analysis, network analysis, artificial intelligence conduce to better elucidate the mechanisms of these combination therapies in disease treatment, which provides new insights for the development of novel active metabolites combination drugs. AMCT rules will hopefully further guide the development of novel combination drugs that will promote the modernization and international needs of TCM.